de Guglielmo Giordano, Matzeu Alessandra, Kononoff Jenni, Mattioni Julia, Martin-Fardon Rémi, George Olivier
Department of Neuroscience, The Scripps Research Institute, La Jolla, California
Department of Neuroscience, The Scripps Research Institute, La Jolla, California.
J Pharmacol Exp Ther. 2017 Sep;362(3):378-384. doi: 10.1124/jpet.117.241042. Epub 2017 Jun 23.
Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 g/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.
塞布瑞诺帕朵是一种新型的痛敏肽/孤啡肽FQ肽（NOP）和阿片受体激动剂，具有镇痛特性，目前正处于治疗慢性和急性疼痛的临床2期和3期试验评估阶段。最近的证据表明，阿片类药物和NOP受体激动作用的联合可能是治疗可卡因成瘾的一种新策略。我们试图通过研究塞布瑞诺帕朵对长期接触可卡因的大鼠可卡因自我给药（0.5毫克/千克/输注）和可卡因条件性复吸的影响来扩展这些发现。口服塞布瑞诺帕朵（0、25和50微克/千克）可逆转给予长期（6小时）接触可卡因的大鼠中可卡因自我给药量的增加，而对加糖炼乳（SCM）的自我给药没有影响。塞布瑞诺帕朵诱导了条件性位置偏爱，但在条件训练期间不影响运动活动。最后，塞布瑞诺帕朵阻断了可卡因觅药行为的条件性复吸。这些结果表明，口服塞布瑞诺帕朵治疗可预防成瘾样行为（即摄入量增加和复吸），提示它可能是治疗可卡因使用障碍的一种新策略。然而，塞布瑞诺帕朵给药后观察到的条件性位置偏爱表明该化合物可能具有一些内在奖赏效应。
